Hindawi Publishing Corporation BioMed Research International Volume 2013, Article ID 484613, 18 pages http://dx.doi.org/10.1155/2013/484613

Review Article Role of Redox Signaling in Neuroinflammation and Neurodegenerative Diseases

Hsi-Lung Hsieh1 and Chuen-Mao Yang2

1 Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Taoyuan, Taiwan 2 Department of Physiology and Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-San, Taoyuan, Taiwan

Correspondence should be addressed to Chuen-Mao Yang; [email protected]

Received 11 September 2013; Revised 30 October 2013; Accepted 21 November 2013

Academic Editor: Sulagna Das

Copyright © 2013 H.-L. Hsieh and C.-M. Yang. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reactive oxygen species (ROS), a redox signal, are produced by various enzymatic reactions and chemical processes, which are essential for many physiological functions and act as second messengers. However, accumulating evidence has implicated the pathogenesis of several human diseases including neurodegenerative disorders related to increased oxidative stress. Under pathological conditions, increasing ROS production can regulate the expression of diverse inflammatory mediators during brain injury. Elevated levels of several proinflammatory factors including cytokines, peptides, pathogenic structures, and peroxidants in the central nervous system (CNS) have been detected in patients with neurodegenerative diseases such as Alzheimer’s disease (AD). These proinflammatory factors act as potent stimuli in brain inflammation through upregulation of diverse inflammatory genes, including matrix metalloproteinases (MMPs), cytosolic phospholipase A2 (cPLA2), cyclooxygenase-2 (COX-2), and adhesion molecules. To date, the intracellular signaling mechanisms underlying the expression of target proteins regulated by these factors are elusive. In this review, we discuss the mechanisms underlying the intracellular signaling pathways, especially ROS, involved in the expression of several inflammatory proteins induced by proinflammatory factors in brain resident cells. Understanding redox signaling transduction mechanisms involved in the expression of target proteins and genes may provide useful therapeutic strategies for brain injury, inflammation, and neurodegenerative diseases.

1. Introduction production of ROS (termed “oxidative stress”) by mitochon- dria and NADPH oxidase (Nox) is usually thought to be In general, inflammation is a protective response to various responsible for tissue injury associated with a range of brain cell and tissue injuries. The purpose of this process is to injury, inflammation, and degenerative diseases such as AD destroy and remove the detrimental agents and injured [5–8]. Moreover, many of the well-known inflammatory tissues, thereby benefiting tissue repair. When this helpful target proteins, including matrix metalloproteinase-9 (MMP- response is uncontrolled, the effect initiates excessive cell 9), cytosolic phospholipase A2 (cPLA2), cyclooxygenase- and tissue damages that result in destruction of normal 2 (COX-2), inducible nitric oxide synthase (iNOS), and tissue and chronic inflammation [1–3]. Moreover, the brain adhesion molecules, are associated with oxidative stress (ROS inflammatory diseases, including Alzheimer’s disease (AD) generation) induced by proinflammatory factors such as and Parkinson’s disease (PD), are characterized by “redox cytokines, peptides, infections, and peroxidants [3, 5, 9]. state” imbalance and chronic inflammation, a major cause Brain cells, especially neuroglial cells, are susceptible to the of cell damage and death. Reactive oxygen species (ROS) injurious effects of oxidative stress. Several studies have arewidelyrecognizedaskeymediatorsofcellsurvival, shown that brain cells like microglia and astrocytes induce proliferation, differentiation, and apoptosis4 [ , 5]. Excessive and release diverse inflammatory mediators in response to 2 BioMed Research International oxidative stress [9–11]. In addition, ROS act as a critical sig- Proinflammatory factors naling molecule to trigger inflammatory responses in central nervous systems (CNS) through the activation of the redox- sensitive transcription factors, including nuclear factor-𝜅B (NF-𝜅B) and activator protein-1 (AP-1) [5, 9]. Thus, this review will focus on many general aspects of oxidative stress regulation and summarize the current progresses regarding the occurrence and effects of redox signals on CNS and their involvement in the expression of inflammatory target proteins in response to proinflammatory factors during brain Neuroglial cells inflammation. Moreover, the pharmacological interventions (microglia and astrocytes) which protect against oxidative stress-induced neuroinflam- mation and neurodegenerative diseases will be discussed.

Inflammatory mediators 2. Role of Neuroglial Cells in CNS Physiological and Pathological Events CNS consists of neurons and glial cells. Among glial cells, astrocytes constitute nearly 40% of the total CNS cell popula- tion in the adult human brain, and they maintain homeostasis in normal CNS. Astrocytes have also been proposed to exert Neuroinflammation a wide range of functions including guidance of the develop- neuronal death ment and migration of neurons during brain development, production of growth factors, maintenance of the integrity of the blood-brain barrier (BBB), and participating in the immune and repairing responses to disease and brain injury [12, 13]. Microglial cells represent resident brain macrophages Figure 1: Schematic presentation of the interaction of the brain and can be transformed into activated immunocompetent cells, including neurons and glial cells. In the central nervous system antigen-presenting cells during the pathological process. An (CNS), proinflammatory factors induce the expression of various increased number of activated microglial cells have consis- inflammatory mediators in neuroglial cells, particularly microglia tentlybeenreportedinPD,whichmayhaveadeleterious and astrocytes. These induced inflammatory mediators from glial effect on dopaminergic neurons [14]. Astrocytes, as well as cells may cause the neuroinflammation or neuronal death, and then microglia, display an array of receptors involved in innate leading to neurodegenerative disorders. immunity, including Toll-like receptors (TLRs), nucleotide- binding oligomerization domains, double-stranded RNA dependent protein kinase, mannose receptor, and compo- cytokinesaswellasneurotoxicsubstances,whicharethought nents of the complement system [10]. One common feature to be responsible for brain injuries and diseases including of a variety of neurodegenerative disorders is the presence trauma,AD,andneuraldeathduetotheexposureofLPS, of a large number of activated glial cells including astrocytes interferon-𝛾,or𝛽-amyloid [18, 19]. Although most studies and microglia that involve the changes of morphology and have demonstrated that microglial cells play an important expression of many inflammation-related proteins. Gliosis, role in neuroinflammation and neurodegeneration, accu- especially astrogliosis, is characterized by astrocytic prolifer- mulating evidence has also demonstrated the characteristic ation, extensive hypertrophy of the cell body, and functional changes of astrocytes in neurodegenerative diseases such as changes, when stimulated with various factors including dementia [10, 11, 20].Recently,wehavedemonstratedthe lipopolysaccharide (LPS), interleukin-1𝛽 (IL-1𝛽), and tumor upregulation of several inflammatory mediators including necrosis factor-(TNF-𝛼)[15, 16]. MMP-9, cPLA2,COX-2,iNOS,andoxidativestressbyvar- Moreover, the cell-cell interactions between glial cells ious proinflammatory factors such as cytokines (e.g., IL- and neurons may be important in the regulation of brain 1𝛽), peptides (e.g., bradykinin (BK) or endothelin-1 (ET- inflammation and neurodegeneration. Many recent reports 1)), infections (e.g., bacteria or virus), and peroxidants implicate that inflammation contributes to a wide variety of (e.g., oxidized low-density lipoprotein (oxLDL)) in rat brain brain pathologies, apparently killing neurons via glia [10, 11, astrocytes [21–29]. More recent data indicated that multi- 17]. Thus, the activated glial cells, especially microglia and ple factors including ROS, MMP-9, and heme oxygenase-1 astrocytes, are thought to play a critical role in the patho- (HO-1)/carbon monoxide (CO) from BK-challenged brain genesis and progression of neurodegeneration (Figure 1). Pre- astrocytes may contribute to the neuronal cell apoptosis viously, many reports have shown that microglial cells may [30]. Together these results implicate that activated neuroglial be a major inflammatory cell of the brain [14]. The activated cells, especially astrocytes, play a key role in the pathogenesis microglia produce several inflammatory mediators including of the CNS inflammation leading to neurodegenerative dis- COX-2/prostaglandins (PGs), iNOS/nitric oxide (NO), or eases (Figure 1). BioMed Research International 3

be deleterious. Recently, accumulating evidence attributes NOS HO-1 the cellular damage in the CNS degenerative disorders to P450 COX GPx Thioredoxin oxidative stress [5–9], suggesting that oxidative stress is an early event in AD [32]. Oxidative stress may be responsible Nox Xox SOD Catalase for brain inflammatory disorders, which cause deleterious Oxidative stress Antioxidants effects during CNS pathogenesis34 [ ]. Furthermore, several reports have shown that ROS levels are increased with age in several major organs including brain [32]. Abnormally elevated ROS is implicated in age-related long-term potenti- Inflammation Anti-inflammation ation (LTP) impairment [35]. ROS further induce expression and activation of proinflammatory factors or inflammatory Figure 2: Oxidative stress and antioxidants imbalance in inflamma- mediators during brain injury and inflammation. Under tion. In inflammation, the balance appears to be tipped in favor of various pathological conditions, excessive amounts of ROS increased oxidative stress by various specialized enzymes, including can damage DNA, lipids, proteins, and carbohydrates leading Nox, Xox, P450, COX, or NOS, either because of excessive ROS to impairing cellular functions and enhancing inflammatory release or inflammatory mediators leading to the amplification reactions [34, 36]. In brains of AD patients, cellular and of the proinflammatory effects. In contrast, induction of several animal models of AD, the elevated levels of these oxidative antioxidants, such as SOD, catalase, GPx, thioredoxin, or HO-1, may reduce ROS generation and attenuate the inflammatory response stress-modified molecules are also detected [32]. Recently, (anti-inflammation). Nox: NADPH oxidase; Xox: Xanthine oxidase; increasing evidence attributes the cellular damage in neu- P450: P450 enzyme; COX: cyclooxygenase; NOS: nitric oxide rodegenerative disorders such as AD and PD to oxidative synthase; SOD: superoxide dismutase; GPx: glutathione peroxidase; stress that leads to generation of ROS associated with brain HO-1: heme oxygenase-1. inflammatory disorders [2, 6]. Thus, these results indicate that oxidative stress (i.e., ROS production) plays an important role in CNS inflammation and neurodegenerative disorders (Figure 4). Oxidative stress activates several intracellular signaling 3. Role of Oxidative Stress (Redox Signaling) cascades that may have a deleterious effect on the cellular in the Brain Inflammation and homeostasis. The molecular mechanisms associated with Neurodegenerative Diseases ROS production (e.g., mitochondrial dysfunction and Nox activation) and its influences have been investigated in var- In CNS inflammation, various proinflammatory factors may ious models of chronic inflammation and neurodegenerative cause the development of an oxidative stress and antioxidants disorders [9]. Recently, there are extensive pieces of literature imbalance, which induces redox signal-dependent expression supporting a role of mitochondrial dysfunction and oxidative of genes for inflammatory mediators or protective antioxi- damage in the pathogenesis of AD [5, 37], and ROS are dants (Figure 2).Theoxidativestress(i.e.,ROSandreactive associated with neuroinflammatory and neurodegenerative nitrogen species (RNS)) is produced by various enzymatic processes [9, 17, 32]. Several proinflammatory factors (e.g., reactions and chemical processes or directly inhaled. ROS LPS and BK) have been shown to induce the expression that are particularly responsible in oxidative stress include ∙− and activation of various inflammatory mediators via a ROS- superoxide anion (O2 ), hydrogen peroxide (H2O2), and ∙ dependent manner in brain cells [25, 36]. In microglial hydroxyl radical ( OH). Furthermore, the RNS include nitric − cells, ROS, as a major signaling molecule, mediate microglial oxide (NO) and peroxynitrite (ONOO ). These oxidative activation induced by proinflammatory mediators such as stresses (i.e., ROS/RNS) are essential for many physiological A𝛽 or LPS [38, 39].However,therolesofoxidativestress functions at low concentrations [2–6] and killing invading microorganisms [31]. However, several lines of evidence that contribute to these events are not well characterized have suggested that the pathogenesis of human diseases is in brain cells including astrocytes. Our recent reports have attributed to increased oxidative stress [2, 31]. Moreover, demonstrated that ROS signals contribute to the expres- oxidative stress has been shown to mediate the pathogenesis sion of many inflammatory genes (e.g., MMP-9) by sev- of neurodegenerative diseases, including PD [6], AD [32], eral proinflammatory factors, including BK[25], LTA [27], 𝛽 and cerebrovascular disorders such as stroke [31]. There and TGF- 1[40] in brain astrocytes. More recent result are several major sources of ROS/RNS generation in the indicates that ROS generation from BK-challenged astro- cells, including Nox, Xanthine oxidase (Xox), P450 enzymes, cytes contributes to neuronal apoptosis through a caspase-3- COX, and NOS (Figure 2), which contribute to several dependent manner [30].Althoughoxidativestressisimpli- physiological and pathological functions including brain cated as a causative factor in neurodegenerative disorders, the inflammation and neurodegeneration8 [ ]. The physiological signaling pathways linking ROS production with neuronal ∙− role of ROS/RNS (along with O2 and NO) also extends celldeatharenotwellcharacterized[6]. Hence, there are to the control of vascular tone in the brain, which is tightly several targets and signals that need to be identified and modulated by the metabolic activity within neurons [6, 33]. explored for the development of therapeutic strategies in the Particularly in the brain, even small redox imbalances can future. 4 BioMed Research International

Proinflammatory factors Proinflammatory factors: cytokines (e.g., IL-1𝛽, TNF-𝛼) 1 𝛽 Nox peptides (e.g., BK, ET- , and A ) HOCl Xox infections (e.g., bacteria, virus) P450 MPO COX peroxidants (e.g., oxLDL, H2O2) NOS ∙− SOD Catalase others (e.g., TGF-𝛽) O2 O2 H2O2 H2O GPx

∙ − ∙ − Neuroglial cell activation L-Arg NO ONOO OH NOS

Figure 3: Major pathways of reactive oxygen (nitrogen) species Redox signals generation and metabolism. Several proinflammatory factors can ∙− (ROS) stimulate O2 generation through activation of several specialized enzymes, such as the Nox, Xox, P450, COX, or NOS. SOD then ∙− converts the O2 to H2O2, which is then converted into the ∙ highly reactive OH or has to be rapidly removed from the system that is generally achieved by catalase or peroxidases, such as the Inflammatory mediators: ∙− ∙ GPx. Further, O2 can be either converted into ROO or can 9 − metalloproteinases (e.g., MMP- ) react with NO to yield ONOO .NOismostlygeneratedbyL- phospholipases (e.g., cPLA ) Arg via NOS. H2O2 can be converted to HOCl by the action of 2 ∙− MPO. myeloperoxidase. O2:molecularoxygen;H2O: water; O2 : cyclooxygenases (e.g., COX-2) ∙ ∙ superoxide radical anion; OH: hydroxyl radical; ROO :peroxyl − NO synthases (e.g., iNOS) radical; H2O2: hydrogen peroxide; ONOO :peroxynitrite;NO: nitric oxide; L-Arg: L-arginine; HOCl: hypochlorous acid. adhesion molecules (e.g., ICAM)

4. Redox Signaling and Proinflammatory Factors in Brain Inflammation and Neurodegenerative Diseases Neuroinflammation ThesenileandneuriticplaqueofADareaccompaniedby Neuronal death inflammatory responses in activated glial cells (i.e., astrocytes Figure 4: Schematic representation of the redox signals (ROS and microglia). In CNS, several cytokines and inflammatory production) and their role in the development of neuroinflamma- mediators produced by activated glia have the potential to tion and neuronal death. Many of the well-known inflammatory initiate or exacerbate the progression of neuropathology [41]. target proteins, such as MMP-9, ICAM-1, VCAM-1, COX-2, and Moreover, traumatic injury to CNS results in the produc- cPLA2, can be upregulated by various proinflammatory factors, tion of inflammatory cytokines via intrinsic (brain cells) including cytokines, peptides, bacterial or viral infection, peroxi- and extrinsic means (by infiltrating macrophages and other dants, via a ROS signal-dependent manner in neuroglial cells. These leukocytes). The expression of many inflammatory mediators inflammatory mediators can cause neuroinflammation and neu- 𝛽 𝛽 𝛼 including cytokines, MMPs, cPLA2,COX-2,andiNOShas ronal death. IL-1 : interleukin-1 ;TNF- : tumor necrosis factor- 𝛼; BK: bradykinin; ET-1: endothelin-1; A𝛽: 𝛽-amyloid; oxLDL: been shown to be regulated by various extracellular stimuli 𝛽 such as proinflammatory cytokines (e.g., IL-1𝛽 and TNF-𝛼), oxidized low-density lipoprotein; H2O2: hydrogen peroxide; TGF- : transforming growth factor-𝛽; MMP-9: matrix metalloproteinase- peptides (e.g., BK, ET-1, and A𝛽), infections (e.g., bacteria 9; cPLA2: cytosolic phospholipase A2; COX-2: cyclooxygenase-2; and virus), peroxidants (e.g., oxLDL and H2O2), and other iNOS: inducible nitric oxide synthase; ICAM: intercellular adhesion. stresses (e.g., TGF-𝛽) in neuronal and neuroglial cells [4– 9, 42](Figure4).

4.1. Cytokines. IL-1𝛽 and TNF-𝛼 are two of the inflamma- The effects of IL-1𝛽 on ROS generation have been reported tory cytokines significantly elevated in neurodegenerative to be associated with brain inflammatory disorders, cancers, diseases such as AD, and they play a central role in initiating and myocardial remodeling [46, 47]. ROS generation by IL- and regulating the cytokine cascades during inflammatory 1𝛽 leads to the expression of several inflammatory genes responses [43]. IL-1𝛽 is a pleiotropic cytokine and classified like MMP-9 which may increase BBB permeability, recruit as a dominant injury biomarker. Furthermore, several studies immune cells infiltrating through BBB into the tissues, and have shown that the level of IL-1𝛽 is elevated in the cere- subsequently result in brain inflammation and edema during brospinal fluid (CSF) of patients with AD, traumatic brain brain injury [6, 34].ROSmayalsoactasaninflammatory injury [44], and stroke [45]. Thus, IL-1𝛽 plays an important signaling factor mediated microglial activation induced by role in both acute and chronic neurodegenerative diseases. IL-1𝛽 [39]. Moreover, in culture of glia/neuron, IL-1𝛽 induces BioMed Research International 5 neurotoxicity through the release of free radicals [48]. In B2-type BK receptors and this type of receptors is found addition, TNF-𝛼 is also produced in response to oxidative only on astrocytes type 1 [57]. The B2 BK receptor is a stress and A𝛽. In brain, TNF-𝛼 is produced by microglia heterotrimeric G-protein-coupled receptor (GPCR) that can and its overproduction has been linked with neuronal cell be coupled to intracellular signaling molecules via interaction death [49]. These studies indicate that cytokines, especially with Gq protein [59]. Activation of BK receptors stimulates 𝛽 𝛼 2+ IL-1 and TNF- , contribute to the CNS inflammation and intracellular signaling molecules, including Ca ,PKCs,and neurodegenerative diseases through redox signalings. MAPKs, in several cell types including astrocytes [57–59]. Activation of these signaling pathways may lead to cell 4.2. Peptides. AD is defined by progressive impairments in survival, proliferation, differentiation, and the expression of memory and cognition and by the presence of extracellular several inflammatory genes such as iNOS and MMP-936 [ , neuritic plaques (A𝛽) and intracellular neurofibrillary tangles 60]. During brain injury, BK has been shown to induce the (tau protein) [5, 32]. Among these molecules, A𝛽 is an expression of several inflammatory genes by increasing ROS insoluble fibrous protein and aggregates sharing specific production [6, 34]. Moreover, Nox is expressed in astrocytes structural traits. It arises from at least 18 inappropriately and contributes to ROS generation [61, 62]. In brain astro- folded versions of proteins and polypeptides present naturally cytes, BK induces the expression of several inflammatory in the body. The misfolded structures alter their proper genes like MMP-9 by ROS-dependent signaling pathways configuration such that they erroneously interact with other [25]. Moreover, ROS released from BK-challenged brain cell components forming insoluble fibrils.𝛽 A has been asso- astrocytes cause neuronal cell apoptosis [30]. These pieces of ciated with the pathology of more than 20 human diseases literature suggest that BK plays an important role in brain including AD. Abnormal accumulation of amyloid fibrils inflammation and neurodegenerative disorders. in brain may play a role in neurodegenerative disorders. 𝛽 Endothelial cells are known to produce vasotone media- Although A peptide is neurotoxic species implicated in the tors such as endothelins (ETs) and NO to maintain hemody- pathogenesis of AD, mechanisms through which intracellular 𝛽 namic responses. The ETs are 21-amino acid vasoconstricting A impairs cellular properties and produces neuronal dys- peptides produced primarily in the endothelium, which play function remain unclear. Accumulating evidence has indi- a key role in vascular homeostasis and have been implicated cated that A𝛽 can stimulate the production of free radicals 𝛽 in brain inflammatory diseases. Among the ET family, the [50]. Interestingly, intracellular A is present in mitochon- bioactivity of ET-1 is mediated through potent vasocon- dria from brains of transgenic mice with targeted neuronal strictor and proinflammatory action in vascular diseases, overexpression of mutant human amyloid precursor protein including the heart, circulation system, and brain [63–66]. and AD patients. Importantly, mitochondria-associated A𝛽, Two types of ET receptors, ET type A (ETA)andtypeB principally A𝛽1 42, was detected as early as 4 months, before – (ETB), are responsible for ET-1-triggered biological effects, extensive extracellular A𝛽 deposits [51]. Moreover, activation 𝛽 which are mediated via G-protein-dependent processes [63– of Nox by A 1–42 results in ROS production in rat primary 65]. In CNS, ET-1 also plays a substantial role in the culture of microglial cells [52]. In mouse models of plaque 𝛽 normal development and CNS diseases. Both endothelial formation, oxidative stress occurs prior to A deposition cells and astrocytes are potential sources of ET-1 release in in a Tg2576 APP transgenic mice [53]. Moreover, increased response to hypoxic/ischemic injury of the brain [66]. On levels of oxidative damage occur in individuals with mild astrocytes, the ETB receptors are predominantly expressed cognitive impairment (MCI), which is often believed to be and modulate postinjury responses of astrocytes in CNS one of the earliest stages of AD [54]. Additionally, glial HO- [67]. Circumstantial evidence has further demonstrated that 1 expression in the MCI temporal cortex and hippocampus overexpression of ET-1 has deleterious effects on astrocytes is also significantly greater than that of the nondemented in ischemic brain [68]. Similarly, ET-1 causes hypertrophy group [55]. These results support A𝛽-induced redox signaling of ETB/GFAP-immunoreactive astrocytes, a typical charac- serving as an early event that leads to the development of the teristic of astrogliosis, in the normal optic nerve, leading to CNS pathological features such as AD. Moreover, glial cells glial scar formation following CNS injury [68]. Endothelial mayplayakeyroleintheevents. ET-1 induces cytokine production such as IL-1𝛽 released In addition to A𝛽 peptide, BK and related peptides are produced and released during trauma, stroke, and neurogenic by astrocytes, which directly contributes to BBB breakdown inflammation56 [ ]. All these pathological processes may during CNS inflammation [69]. These findings further imply be involved in tissue remodeling, which were regulated by the involvement of ET-1 in the CNS inflammation and MMPs. Moreover, astrocytes possess receptors for numerous diseases. transmitters such as glutamate and BK [57]. These peptides mediate several inflammatory responses including increasing 4.3. Infections. Bacterial infections have been shown to be vasodilatation and vascular permeability, promotion of fluid involved in brain inflammation70 [ ]. A well-known endo- secretion and ion transport, and eliciting itching and pain toxin from Gram-negative bacteria, LPS, regulates the expres- at the sites exposed to noxious stimuli. Thus, the elevated sion of inflammatory proteins associated with inflammatory level of BK plays a key role in the initiation of inflamma- diseases. Many studies have also shown that ROS are the tory responses in target tissues, including CNS. It is well major signaling molecule which mediates microglial activa- established that BK interacts with two BK receptor subtypes, tion induced by inflammatory mediators, including LPS [71]. including BK B1 and B2 [58]. Astrocytes are known to express However, the signaling mechanisms of which activated brain 6 BioMed Research International cellsinresponsetoGram-positivebacterialinfectionremain years old of age group are susceptible to these infections undefined. Gram-positive bacterial infections of CNS occur and may develop permanent neurological sequelae or even in bacterial meningitis and brain abscess, being localized to succumb to such disorders [86]. In 1998, an EV71 outbreak the membranes surrounding the brain and in its parenchyma infected more than 130,000 children resulted in 78 fatali- [72]. Lipoteichoic acid (LTA), an amphiphilic polymer, is ties. Since then, EV71 infection has recurred every year in embedded in-cell wall of Gram-positive bacteria [73]. The Taiwan and EV71 outbreaks have been periodically reported Gram-positive bacterium Streptococcus pneumoniae is the throughout the world, representing a major public health most common cause of acute bacterial meningitis worldwide concern particularly in the Asia-Pacific regions including [74], revealing a close relationship between LTA challenges Taiwan, Malaysia, Singapore, Japan, and China [85, 87]. The and CNS diseases. For the initiation of LTA signaling, TLRs emerging evidence suggests that ROS affect the interaction are believed to be responsible for LTA recognition challenged between host and viral pathogens. Recently, EV71 has been by Gram-positive bacteria such as Staphylococcus aureus shown to induce oxidative stress-dependent viral replication and Streptococcus pneumoniae [75]. Upon binding to TLR in human neuroblastoma SK-N-SH cell line [88]. Similarly, heterodimers (i.e., TLR2/TLR1 or TLR2/TLR6 complex), LTA JEV is a single-stranded, positive-sense RNA virus belonging exerts a sequential activation of members of IL-1 receptor- to the family Flaviviridae. JEV is transmitted between animals associated kinase (IRAK) family and tumor necrosis factor and humans by culex mosquitoes [89]. After the bite of receptor-associated factor 6 (TRAF6), mediated by a TLR an infected mosquito, JEV amplifies peripherally producing adaptor protein MyD88. Ultimately, TLR signalings activate transient viremia before entering into CNS [89]. The principal MAPK family and NF-𝜅B, leading to modulation of gene target cells for JEV are localized in CNS, including neurons expression of cytokines and other inflammatory proteins and astrocytes [90]. Several lines of evidence suggest that [76]. Among the diverse cell types in CNS, glial cells such JEV frequently causes severe encephalitis in the world, as astrocytes and microglia are regarded as targets in Gram- especially in Eastern and Southeastern Asia. The infection positive bacterial infection [77–79]. Several lines of evidence with JEV is characterized by clinical manifesting with fever, suggest a causal relationship between LTA challenges and headache, vomiting, signs of meningeal irritation, and altered the CNS diseases, which involves glial activation and TLR2 consciousness leading to high mortality [89, 90]. The gen- signalings [77–79].TLRsignalingsinastrocyteshavebeen eration of ROS plays an important role in diverse cellular showntobeinvolvedininflammatoryresponsesinCNS[80], functions including signal transduction, oxygen sensing and accompanied with upregulation of genes with inflammatory host defense during infection by viruses such as JEV [91]. and proapoptotic effects [81]. The pathogenic progression InCNS,JEVinfectionhasbeenshowntoupregulateMMP- involves glial activation and TLR2 signalings stimulated by 9 gene expression through ROS-dependent pathways in LTA, which are linked to inflammatory neurodegeneration brain astrocytes [28]. These findings concerning JEV-induced [82]. Additionally, LTA exhibits detrimental effects on brain expression of inflammatory genes in brain astrocytes imply cellular functions, including induction of apoptosis, produc- thatJEVmightplayacriticalroleinthebraininflammation tion of oxidative stresses, and disruption of BBB following and neurodegenerative diseases. group B Streptococcus or Staphylococcus aureus challenge in CNS [82]. Although the effects of LTA on ROS generation 4.4. Peroxidants. Oxidative stress may cause production of have been reported in several cell types such as renal diseases several peroxidants such as oxidized lipoprotein. Clinical [83], LTA-induced brain cell responses through the ROS reports reveal that the patients with AD exhibit an increased signals are not well characterized. Recent report indicates oxidation of lipoproteins potentially toxic to neurons in that LTA-induced MMP-9 expression is mediated through CNS [92]. Among these, the oxidized low-density lipopro- Nox2-derived ROS generation in brain astrocytes [27]. These tein (oxLDL) is a well-known predominantly risk factor data suggest that targeting LTA and its specific signaling of atherosclerosis, which has been reported to participate components could yield useful therapeutic targets for CNS in the progression of the CNS diseases. In CNS, oxLDL inflammatory diseases upon infection with Gram-positive exhibits detrimental effects on brain cell functions, including bacteria. induction of apoptosis, disruption of capillary homeostasis, Moreover, increasing evidence has shown that viral andalterationofinflammatoryproteinactivityinvarious infections such as Japanese encephalitis virus (JEV) and brain cells [93]. Furthermore, in patients with cerebral infarc- Enterovirus 71 (EV71) may contribute to several inflam- tion, oxLDL is present in brain parenchyma and stimulates matory responses in CNS [28]. Neurotropic viruses can astrocytes to secrete interleukin-6 [94]andmayserveasan cause massive neuronal dysfunction and destruction that lead indicator to reflect the level of oxidative stress95 [ ]. In brain to neurological diseases. EV71, a single-positive-stranded astrocytes, oxLDL can induce MMP-9 expression and cell RNA virus, belongs to the Enterovirus B genus of the migration, which plays a critical role in the progression of Picornaviridae family [84]. EV71 and Coxsackievirus A16 inflammatory diseases and remodeling processes in target (CVA16) are the major causative agents of hand-foot-and- tissues, including CNS [29, 96]. These findings suggest mouth disease (HFMD) that is usually mild exanthematous that peroxidants like oxLDL might play a key role in the infection and self-limiting in the young children. However, progression of the CNS diseases and also that targeting these EV71, but not CVA16, can progress to severe neurological peroxidants-stimulated signaling components may provide diseases including fatal encephalitis, aseptic meningitis, and useful therapeutic strategies for brain inflammation and fatal neurogenic pulmonary edema [85]. Children under 5 neurodegenerative diseases. BioMed Research International 7

4.5. Others. In addition to these well-known factors, there and mechanism of these inflammatory mediators in the brain are many factors that may also contribute to neuroinflam- inflammation and neurodegeneration and whether oxidative matory responses. Among these, TGF-𝛽 has been implicated stress plays a crucial role in these events. to participate in the responses. TGF-𝛽 binds to two ser- ine/threonine kinase receptors which consist of TGF-𝛽RI and 5.1. Matrix Metalloproteinases. MMPs are a large family of TGF-𝛽RII. During ligand binding, TGF-𝛽RII phosphorylates zinc-dependent endopeptidases, which play an important TGF-𝛽RI and activates Smad-dependent intracellular signal- role in the turnover of extracellular matrix (ECM) and ing pathways and thus leads to expression of several genes [97, pathophysiological processes [104]. To date, 24 MMPs have 98]. In addition to activation of Smad-dependent pathways, been identified in mammals. Among these MMPs, some TGF-𝛽 can affect several signal transduction pathways in are membrane-type MMPs which are anchored to the cell a Smad-independent manner, such as MAPKs [97, 98]. surface and others are secreted into the extracellular space. In In human gingival and skin fibroblasts, both p38 MAPK general, MMPs are released as inactive proform MMPs and and Smad3 cooperate in regulating TGF-𝛽-induced MMP- activated by proteolytic cleavage of the N-terminal domain. 13 expression, whereas ERK1/2 cooperates with Smad3 in In gelatinase subfamily of MMPs (i.e., MMP-2 and MMP- 2+ regulating connective tissue growth factor expression [99]. 9), the catalytic domain that contains the Zn binding site Recently, increasing evidence has attributed the cellular and repeats of fibronectin motifs allowing the ability to bind damage in neurodegenerative disorders to oxidative stress their major substrate gelatin. MMP-9 (gelatinase B; 92kDa) leading to generation of ROS that are responsible for brain is usually low and its expression can be induced by various inflammation and neurodegenerative disorders6 [ , 34]. TGF- proinflammatory factors such as cytokines. The other class 𝛽 can stimulate ROS production, which participates in the of gelatinase, MMP-2 (gelatinase A; 72 kDa), is constitutively expression of diverse inflammatory genes such as MMPs in expressed in several cell types and usually not inducible. In the processes of several human inflammatory diseases100 [ ]. CNS, MMPs, especially, MMP-9 are implicated in several In brain astrocytes, TGF-𝛽1hasbeenshowntoinduceinflam- important physiological events, including morphogenesis, matory protein expression via a ROS-dependent manner wounding healing, and neurite outgrowth [105]. Moreover, [40]. These results suggest that TGF-𝛽1 may play a key role upregulation of MMP-9 may contribute to the pathogenesis in the process of brain inflammation and neurodegenerative of several CNS diseases such as stroke, AD, multiple sclerosis, diseases. and malignant glioma [105]. Several proinflammatory factors including cytokines, endotoxins, and oxidative stress have been shown to upregulate MMP-9 in astrocytes in vitro 5. Role of Redox Signaling in the Regulation of [106, 107], implying that MMP-9 activity may be regulated by Inflammatory Mediators diverse factors in CNS during neuroinflammation. Moreover, many proinflammatory mediators like cytokines and BK Neuroinflammation is an active defensive process against induce the expression of MMP-9 during brain injury by diverse insults, metabolic and traumatic injuries, infection, increasing ROS production [25, 62]. Recently, upregulated and neurodegenerative diseases. Although neuroinflamma- MMP-9andROSgenerationfrombrainastrocyteshavebeen tion serves as a neuroprotective mechanism associated with reported to contribute to neuronal cell death in vitro [30]. repair and recovery, it can also cause brain damage [101]. These studies suggest that upregulation and activation of However, if inflammation in the brain is chronic or inappro- MMP-9 by proinflammatory factors are mediated through priately controlled, it may become detrimental to neurons, oxidative stress (ROS production) during brain injury and thus representing one of the various pathological insults inflammation (Figure 4). Therefore, the inhibition of MMP- induced by various proinflammatory factors and by inflam- 9-mediated inflammatory pathways may provide therapeutic matory mediators in CNS [101]. Experimental and clinical strategies to brain inflammation and neurodegenerative dis- studies have shown that various inflammatory mediators eases. are present in brain, CSF, and blood in brain injury. In particular, the histological analysis of human brain from 5.2. Cytosolic Phospholipase A2. There are three forms of individuals with brain disorder such as AD or epilepsy of phospholipase A2 (PLA2) superfamily including the secretory various etiologies strongly suggests the existence of a chronic PLA2,typeIVPLA2,alsoknownascPLA2,andcalcium- inflammatory state in the brain almost invariably associated independent PLA2 in mammalian cells [108–110]. The sec- with neuronal loss or reactive gliosis [102]. In experimental retary PLA2 (sPLA2) is expressed in a variety of cell types models of rodent brain seizures, a variety of inflammatory and it has no preference for AA at sn-2 position, requires 2+ mediator mRNAs and protein levels are rapidly increased millimolar amounts of Ca for activity and is sensitive to after the induction of seizures, including MMPs (e.g., MMP- sulfhydryl reducing agents, such as dithiothreitol (DTT), and 9, especially), multiple forms of PLA2 (e.g., cPLA2), COX-2, isresistanttoheatoracidconditions[109]. The calcium- 2+ NOS (e.g., iNOS), and adhesion molecules (e.g., ICAM-1 and independent PLA2 (iPLA2)doesnotrequireCa for catalytic VCAM-1) [102, 103]. After expression of these inflammatory activity. The iPLA2 prefers plasmalogen substrates and does mediators, several CNS damaging factors will be produced not appear to have a preference for the type of fatty acid at the such as cytokines shedding by MMPs, arachidonic acid sn-2 position. The third class is the novel and high molecular (AA)/PGE2 releasing by cPLA2/COX-2 system, and NO weight (85 kDa) cPLA2.ThecPLA2 catalyzes the hydrolysis of generation by NOS [102, 103]. Herein, we reviewed the role the sn-2 position of membrane glycerophospholipids, leading 8 BioMed Research International to production of free fatty acids and lysophospholipids. This Previous studies showed that COX-2 immunoreactivity is a reaction is of particular importance if the esterified fatty acid characteristic finding in the synovial macrophage of patients is AA, which is converted by downstream metabolic enzymes with arthritis as well as in other forms of inflammation. to various bioactive lipophilic compounds called eicosanoids, Moreover, several lines of evidence have confirmed COX-2 as including PGs and leukotrienes (LTs) [110]. PLA2 could be a major therapeutic target for the treatment of inflammatory the initial and rate-limiting enzyme in this conversion. The disorders such as arthritis [119, 122]. Recently, the mice with increase in cPLA2 activation and expression following exter- homozygous deletion of the COX-2 gene suppress endotoxin- nal stimuli, including proinflammatory cytokines, growth induced inflammation [123]. In brain, expression of COX- factors, and microbial toxin, is often observed in several 2 leads to increased production of prostanoids which are systems [111]. Among these enzymes, cPLA2 is the only potent inflammatory mediators, and upregulated COX-2 one that plays a key role in mediating agonist-induced AA expression has been reported in neurodegenerative disorders release for eicosanoid production in various cell types [112]. [124]. Moreover, upregulation of COX-2 and PGE2 release Several studies have indicated that cPLA2 is constitutively by viral infection such as EV71 have been reported in expressed in the cytosol of most resting brain cells and brain astrocytes and human neuroblastoma cells via diverse tissues. In brain, cPLA2 has been shown to co-localize with signaling pathways [125, 126]. Upregulation of COX-2/PGE2 glial fibrillary acidic protein (GFAP), a principal marker for by ET-1 via MAPK-dependent NF-𝜅Bpathwayinbrain brain astrocytes [113]. Moreover, under brain inflammatory microvascular endothelial cells [127]. A recent report also and neurodegenerative conditions such as AD, there is an indicates that the ROS-induced COX-2 expression can be increase in immunoreactivity to cPLA2 in astrocytes from found in ALS [128]. However, the expression of COX-2 the cortex of patients [114, 115]. A variety of proinflamma- appears to be strongly induced and activated during AD, tory factors including IL-1𝛽,TNF-𝛼, or BK may exert as indicating the importance of inflammatory gene pathways as modulators of cPLA2 activity and/or expression in various a response to brain injury [118]. Thus, COX-2 may play an cell types including astrocytes [23, 111]. Upregulation and important role in the development of brain inflammation and activation of cPLA2 leading to PGE2 production have been neurodegenerative diseases. implicated in a number of neurodegenerative diseases [111, 114, 115]. Recently, PGE2 production and cPLA2 activation 5.4. Nitric Oxide Synthase. NO is a free radical that displays have also been shown to regulate the CREB-dependent iNOS diverse bioactivity in various organ systems, including CNS. expression in microglia [116]orcPLA2 expression in amnion Depending on the concentration, excess NO levels are impli- fibroblasts [117]. However, a series of highly reactive PGs, free cated in the pathogenesis of CNS diseases including ischemia, fatty acids, lysophospolipids, eicosanoids, platelet-activating trauma, neuroinflammatory, and neurodegenerative diseases factor, and ROS, all generated by enhanced PLA2 activity [129–131]. Production of NO from L-arginine is catalyzed by and AA release, participate in cellular injury, particularly in NOS. The level of iNOS in healthy brain is undetectable. neurodegeneration [118]. Thus, cPLA2 seemstofunctionasa AccumulatingevidencesupportstheroleofiNOSinthe crucial upstream regulator of the production of eicosanoids pathogenesis of CNS disorders. In CNS, upregulation of iNOS during brain inflammation and is correlated to the process in various cell types, including astrocytes and microglia, is of neurodegenerative diseases (Figure 4). The inhibition of proposed to be the leading source of NO production during cPLA2-mediated pathways may provide a therapeutic strat- neuroinflammation [132]. Furthermore, knockout strategies egy to brain inflammation and neurodegenerative diseases. of iNOS gene protect against focal cerebral ischemia and LPS challenges [133, 134]. iNOS is induced by a variety of 5.3. Cyclooxygenase-2. COX, known as a prostaglandin- stimuli, such as viral and bacterial infections, cytokines, cell- endoperoxide synthase, is a rate-limiting key enzyme in cell contact, and neurotoxins [131]. The consequent product − the synthesis of PGs. In this process, PLA2 catalyzes the NO reacts with superoxide to form peroxynitrite (ONOO ), release of AA from membrane phospholipids, while COX the most toxic derivative of NO (Figure 3). As for the involve- catalyzes the conversion of AA into PGs [119]. Significant ment of NO derivatives in neuropathology, many studies − advances have been made in understanding the role of have revealed that the reference of iNOS/NO/ONOO plays COX in certain biologic processes, including inflammation, an important role in neurodegenerative disorders [131]. angiogenesis, development, and several homeostasis [119]. However, following inflammatory insults, reactive astrocytes COX exists in two isoforms: COX-1, which is expressed con- express iNOS, which causes the neuronal damage associated stitutively under normal conditions in most tissues, mediates with cerebral ischemia and/or demyelinating diseases [132]. regulating normal physiological responses, and controls renal In CNS, appearance of iNOS in astrocytes is related to homeostasis, and the inducible COX-2, is not detectable several neurodegenerative diseases such as ALS [130]and in most normal tissues or resting cells, but its expression multiple sclerosis (MS) [129]. These findings imply that can be induced rapidly by a variety of stimuli including astrocytes are the leading regulators in neurodegenerative cytokines, bacterial or viral infections, and other mediators to diseases. Moreover, activation of astrocytes has been reported produce PGs during inflammation120 [ ]. In addition, COX-2 to involve in the expression of inflammatory genes. It has gene promoter which contains multiple regulatory elements been well established that the regulation of iNOS expression has been shown to be regulated by different transcription is mediated via tyrosine kinases such as JAK, MAPKs, ROS, factors, including NF-𝜅B, AP-1, and cyclic AMP-response and various transcription factors including STAT-1, NF-𝜅B, element binding protein (CREB) in various cell types [121]. and AP-1 in astrocytes [131]. Increasing evidence suggests BioMed Research International 9 that activation of signal transduction pathways like c-Src, association with inflammatory mechanisms. In the events, PI3K/Akt, and MAPK cascades contributes to activation of theHSPsplayacrucialroleinpreventingproteinmisfolding astrocytes and microglia, leading to expression of inflam- and inhibiting apoptotic activity and represent a class of pro- matory proteins and advanced damage in neurodegenerative teins potentially involved in PD pathogenesis [143]. Recent diseases [25, 26, 135]. studies have shown that HSPs are colocalized in protein aggregates in AD, PD, and other neurodegenerative disorders [144, 145]. Many experimental findings have demonstrated 5.5. Adhesion Molecules. Cell adhesion molecules play an that selective overexpression of HSP70 prevents the disease important role in inflammatory responses. Leukocytes con- progression in various animal models and cellular models tinuously circulate throughout the body in order to come in [145]. Furthermore, HSP70 dysfunction activates intracel- contact with antigens sequestered within tissues. To enter tis- lular signaling like NF-𝜅B that can also promote neurode- sues, circulating leukocytes migrate from the blood between generation [146]. Thus, the expression of HSP70 may prove vascular endothelial cells and into the tissue [136]. During this diagnostic and prognostic values in inflammatory conditions migration, leukocytes initially bind to endothelial cells via and therapeutical applications are being considered on the low-affinity adhesion molecules. The low-affinity adhesion basis of these reports. in combination with the force of the blood flow results in rolling leukocytes on endothelial cells. Subsequently, adhe- sion molecule affinity is upregulated and leukocytes firmly 6. Redox Signal-Mediated adhere to the endothelium [136]. Finally, bound leukocytes Signaling Transduction migrate between the endothelial cells and into the tissue. The vascular cell adhesion molecule 1 (VCAM-1) isone Recently, increasing evidence has demonstrated that oxida- of the inducible cell transmembrane glycoproteins of the tive stress (ROS generation) also plays a key signaling immunoglobulin supergene family expressed on several cell molecule in regulation of various inflammatory mediators typesandplaysanimportantroleinanumberofinflam- in several cell types. Although many cells from brain tissue matory and immune responses [137]. It was first identified can produce various inflammatory mediators [42, 105], the as an adhesion molecule induced on endothelial cells by intracellular signaling mechanisms responsible for the regu- proinflammatory cytokines or LPS [138]. VCAM-1 expres- lation of diverse inflammation-relating mediators expression sion is induced on endothelial cells during inflammatory induced by proinflammatory factors in brain cells like astro- bowel disease, atherosclerosis, and infections [139]. Upregu- cytes are not completely characterized. Next, we review some lation of VCAM-1 expression on cytokine-triggered vascular signaling molecules in several inflammatory target protein endothelial cells enhances the targeted transmigration of expressions induced by proinflammatory factors in brain PMNs into extravascular space of inflammation [137]. In cells. brain, proinflammatory cytokine-mediated expression of cell surface adhesion molecules plays a key role in endothelial 6.1. Mitogen-Activated Protein Kinases. Many proinflamma- cell injury, leading to vascular inflammation and the devel- tory cytokines and chemokines transducer signals are medi- opment of many cerebrovascular diseases [140]. Moreover, ated via activation of MAPKs pathways. There is growing astrocytes can be induced by viral infections to express the evidence that members of the MAPK family may play a cen- adhesion molecules. Upregulation of adhesion molecules tral role in neurodegeneration [147]. MAPKs are important such as ICAM-1 (intercellular adhesion molecule 1) and components of signaling modules activated by neurotrans- VCAM-1 in astrocytes is required for monocyte-astrocyte mitters, cytokines, and growth factors, as well as chemical and interaction which increases infiltration of monocytes into the mechanical stressors. In mammals, three groups of MAPKs CNS observed in the patients with HIV-1 dementia [141]. have been identified: the extracellular signal-regulated pro- HIV-1 Tat enhances monocyte adhesion by upregulation tein kinases (ERKs), the c-Jun NH2-terminal kinases (JNKs), of ICAM-1 and VCAM-1 genes via a ROS-dependent NF- and the p38 MAPK. ERK is activated by diverse stimuli, 𝜅Bactivationinastrocytes[141]. Understanding the role of including growth factors and cytokines [147]. The p38 MAPK ROS in proinflammatory factor-mediated adhesion molecule is activated by cellular stresses, including cytokines, LPS, expression and subsequently increased adhesion of monocyte growth factors, and UV radiation. The JNK is activated to brain cells provides an occasion for the development by many of the same stimuli that activate p38 MAPK, of anti-inflammatory compounds that may be useful as such as cellular stresses and various cytokines. Moreover, therapeutic strategies for the CNS inflammation and ROS- abnormal MAPK regulation might be implicated in CNS associated neurotoxicity. injury and inflammation [148]. Several mediators such as BK have been reported to act as an important proinflammatory 5.6. Stress Protective Proteins. In contrast with inflammatory factors through activation of MAPK cascades in different proteins, recent reports indicate that the ROS can also cell types [21–26]. In brain cells, the activation of ERK1/2 induce several stress protective proteins, such as HO-1 and is mainly associated with proliferation, differentiation, and heat-shock proteins (HSP70 in particular), which may exert development in response to nerve growth factors. In contrast, protective effects from the deleterious effects of inflamma- the JNK and p38 MAPK signaling pathways are activated tion [142]. Abnormal protein folding has been shown as a by various environmental stress and inflammatory factors cause of various diseases like neurodegenerative diseases in that have been shown to promote neuronal cell death [149]. 10 BioMed Research International

Moreover, the JNK and p38 MAPK signaling cascades can Proinflammatory factors also be strongly activated by stress-induced ROS production cytokines, peptides, or a mild oxidative shift of the redox state [28]. Both infections, peroxidants, and JNK and p38 MAPK are recognized as contributors to oxidative stress neurodegeneration by their ability to mediate intracellular stress events in transgenic mouse models of AD [19]. The p38 MAPK activation and COX-2 and PGE2 induction are served as contributors to neuronal damage in AD in response Signaling molecules to oxidative stress [150]. ROS In nonneural cells like astrocytes, many studies have EGFR/PDGFR found that A𝛽 peptide can activate astrocytes, including PI3K/Akt morphological alterations, cytokine induction, NO release MAPKs [151], and chemokine and matrix-degrading proteinases pro- duction [152]. These findings further indicate that induction 𝛽 of several inflammatory mediators by the A -stimulated Transcription factors activation of MAPKs in glial cells may be involved in AD (e.g., NF-𝜅B, AP-1) progression. Moreover, our recent reports in astrocytes have demonstrated that the proinflammatory factors including TGF-𝛽 and BK can induce many inflammatory mediators Inflammatory target proteins such as MMP-9 expression through the ROS-dependent MAPK cascades [40]. These results suggest that upregulation of inflammatory mediators via ROS-mediated activation of MAPKs in astrocytes might play a key role during the Neurodegenerative diseases CNS inflammation and neurodegeneration. Moreover, these Alzheimer’s disease results also implicate that the distinct groups of MAPKs Parkinson’s disease are activated by a ROS-dependent manner which contribute Amyotrophic lateral sclerosis to the expression of various inflammatory genes and are Multiple sclerosis dependent on the external stimuli during brain inflamma- tion. Thus, ROS may mediate MAPKs activation and expres- Figure 5: Proposed mechanisms of proinflammatory factors- stimulated activation of various signaling molecules and tran- sion of inflammatory genes in response to proinflammatory scription factors leading to the expression of inflammatory target mediators in the CNS inflammatory disorders (Figure 5). genes in brain resident cells. The tracellularin signaling molecules include ROS, EGFR/PDFER, PI3K/Akt, and MAPKs. Oxidative 6.2. Transactivation of Receptor Tyrosine Kinases. Cross- stress may regulate these signaling pathways leading to activation communication between different signaling systems allows of transcription factors such as NF-𝜅BandAP-1andrecruit- the integration of the great diversity of stimuli that a cell ment of coactivator p300 in the transcription initiation complex. receives under varying physiological situations. The most Ultimately, upregulation of diverse inflammatory target proteins direct mechanism is receptor heterodimerization that is can cause the pathogenesis of several neurodegenerative diseases. EGFR: epidermal growth factor receptor; PDGFR: platelet-derived well described for members of the epidermal growth factor 󸀠 growth factor receptor; PI3K: phosphoinositide-3 -kinase; MAPKs: receptor (EGFR) family [153]. In addition to growth factor 𝜅 𝜅 receptor tyrosine kinases (RTKs) cross-talk, also completely mitogen-activated protein kinases; NF- B: Nuclear factor- B; AP-1: activator protein-1. unrelated cell surface receptors are able to communicate and influenceeachother,whichplayakeyroleinthetransmission of information from outside the cell into the cytoplasm and nucleus. A variety of cytokines and growth factors that subsequent downstream effects including the stimulation of act as respective receptors have been reported to induce cell migration and invasion [158]. However, receptor cross- production of ROS in nonimmune cells. The prototype for talk can also occur in a ligand-independent manner involving such a pathway is the GPCR-induced transactivation of EGFR for instance, non-RTKs such as c-Src [159]. Production of signal [154]. Treatment of cells with GPCR agonists induces ROS results from the activation of signaling through the phosphorylation of the EGFR by metalloprotease-dependent EGF and PDGF receptors [160]. In addition, ROS have release of EGF-like ligands such as HB-EGF, thereby cou- been shown to stimulate c-Src-dependent transactivation pling GPCRs to EGFR characteristic downstream signaling of PDGFR𝛼 [161]. Accumulating evidence has shown that pathways such as MAPKs or PI3K/Akt pathway [155]. In PKC-dependent activation of Nox is essential for PDGF- addition to the EGFR, other RTKs have been shown to be stimulated ROS generation, which is important for PDGF- activated in response to GPCR stimulation, comprising the induced MAPKs activation [162]. In the adult CNS, the EGFR Trk receptor [156] and platelet-derived growth factor receptor pathway is highly upregulated and activated in astrocytes (PDGFR) [157]. Previous studies have shown that in devel- followingneuronalinjury[163]. Activation of the EGFR oping carcinoma cells, the early effects of COX-2-derived pathway triggers quiescent astrocytes to become reactive PGE2 and lysophosphatidic acid are in part mediated by the astrocytes that appear to be destructive to neurons in the EGFR or PDGER, and this transactivation is responsible for adult CNS [163]. Regulation of RTKs such as EGFR in BioMed Research International 11 astrocytes may be a new therapeutic strategy for the treatment stress response, and apoptosis [167–169]. One important and of neural disorders. These studies suggest that growth factor widely investigated transcription factor which is NF-𝜅Bisa RTKs may play a pivotal role in mediating inflammatory major participant in signaling pathways governing cellular genes regulation through ROS signal in several diseases responses to environmental (oxidative) stresses [168]. The including the CNS disorders (Figure 5). nuclear translocation and activation of NF-𝜅Binresponse to various stimuli, such as proinflammatory cytokines, LPS, 󸀠 6.3. Phosphoinositide-3 -Kinase (PI3K)/Akt Cascade. The and oxidative challenge (ROS production), are sequentially 󸀠 phosphoinositide-3 -kinase (PI3K)/Akt cascade, the com- organized at the molecular level [168]. Moreover, NF-𝜅Bact mondownstreamsignalofEGFandPDGFreceptors,isa as a positive regulator in the expression of many inflamma- cell survival pathway and regulated by various growth factor tory genes such as COX-2 involved in chronic inflammatory receptor-dependent mechanisms. Recent studies suggested diseases [169]. Cytokines such as IL-1𝛽 and TNF-𝛼 have been that numerous components of the PI3K/Akt pathway play a shown to activate NF-𝜅B leading to upregulation of various crucial role in the expression and activation of inflammatory NF-𝜅B-dependent genes in several cell types [168]. It is of mediators, inflammatory cell recruitment, immune cell interest that many of the genes regulated by these MAPK function, and tissue remodeling in chronic inflammatory pathways are dependent on NF-𝜅B for transcription and lead diseases. In astrocytes, we demonstrated that ET-1 induced to expression of inflammatory genes such as MMP-9 at the iNOS expression and NO production through PI3K/Akt transcriptional level [169, 170]. In astrocytes, various stimuli cascade [26]. Moreover, PI3K/Akt cascade contributes to can induce the expression of several inflammatory mediators, the expression of various inflammatory mediators induced including MMP-9, cPLA2,COX-2,andiNOS,throughROS- by several proinflammatory factors in brain cells including mediated activation of NF-𝜅Bmanner[40, 62]. astrocytes [125, 127]. Selective PI3K inhibitors such as In addition, activator protein-1 (AP-1) is a sequence- wortmannin and LY294002 have been developed that specific transcriptional activator mainly composed of mem- reduce inflammation and some characteristics of disease in bersoftheFos,Jun,andATF-2families.Theseproteins experimental animal models. In addition, ROS induction is associate to form a variety of homodimers or heterodimers often accompanied by the activation of PI3K/Akt cascade. For that bind to an AP-1 binding element within the promoter example, LY294002 has been shown to reduce chemokine- region of inflammatory genes such as COX-2 and MMP- induced ROS generation in phagocytes [164], which was 9. It is a well-known redox-regulated transcription factor further confirmed by studies using PI3K knockout mice. for the expression of several AP-1-dependent genes induced Many studies have indicated the ROS generation induced by diverse stress signals such as ROS generation associated by cytokines, PDGF, or VEGF in several cell types, which is with physiological and pathological events [25, 62, 170]. reduced by inhibition of PI3K activity, suggesting that PI3K Several reports indicate that AP-1 is also involved in the is involved in the ROS production induced by cytokines pathogenesis of brain inflammation (Figure 5). Many studies ∙− and growth factors. In addition to the role of PI3K/Akt have demonstrated that ROS signals (e.g., O2 and H2O2) cascade in ROS production, several reports support that the contribute to the expression or activation of AP-1 proteins opposite hierarchical relationship exists between ROS and (e.g., c-Fos) [62]. Recently, Kim et al. demonstrated that apoc- PI3K/Akt cascade. PI3K/Akt was activated in response to ynin (a Nox inhibitor) shows potential antioxidant activities the exogenous treatment of H2O2 in several cell types [165]. and inhibitory effects on the activation of redox-sensitive Moreover, ROS have been shown to regulate phosphorylation transcription factors, such as AP-1, induced by proinflam- of Akt [166] and then induce the expression of inflammatory matory stimuli such as TNF-𝛼 [171]. The reports indicate genes associated with inflammation in various cell types. that CSE induces cPLA2 expression through the production Taken together, these results implicate that ROS-dependent of ROS and subsequent activation of the MAPK pathway PI3K/Akt cascade or PI3K/Akt-mediated ROS signal may andAP-1inhumantrachealsmoothmusclecells[172]. In be critical for regulating the expression of inflammatory astrocytes, we have demonstrated that AP-1 participates in proteins in the brain inflammation and neurodegenerative the expression of several genes, including MMP-9 and HO- disorders (Figure 5). 1, by BK through ROS-dependent manner [25, 62]. These resultsimplicatethatROSplayacentralroleinregulating 6.4. Transcription Factors. The progressive increase of oxida- AP-1 activation or expression and lead to inflammatory genes tive stress during injuries not only causes oxidative damage expression in brain inflammation and neurodegenerative to cellular macromolecules, but also modulates the pattern of disorders (Figure 5). gene expression through functional alterations of transcrip- tion factors. Here we focus on the roles of many transcription 6.5. Transcription Coactivators. The transcription coactivator factors (e.g., NF-𝜅B and AP-1), which are well known to be p300/CREB binding protein (CBP) is vital for the coacti- modulated during oxidative stress associated with physiolog- vation of several transcription factors such as NF-𝜅Band ical and pathological events [32]. The transcription factors AP-1 in the transcription machinery, which has a significant such as NF-𝜅B and AP-1 play a key role in the regula- role in the activation of transcription factor-mediated gene tion of several gene expressions including proinflammatory expression for proinflammatory factors [173–175]. The p300 cytokines, adhesion molecules, chemokines, growth factors, protein is a key regulator of RNA polymerase II-mediated and inducible enzymes (e.g., MMPs, cPLA2,COX-2,and transcription. Several studies indicate that p300 participates iNOS) during inflammation, immunity, cell proliferation, in the expression of inflammatory genes induced by cytokines 12 BioMed Research International and growth factors. Furthermore, the transcriptional cofactor of this review is on glial cells and their effects on the CNS p300/CBP is an important component of the transcriptional disorders. Moreover, this review summarized the interplay machinery that participates in regulation at the levels of between oxidative stress and neuroinflammation via ROS both chromatin modification and transcription initiation production which contributes to neurodegeneration, thereby [173–175]. Previous studies have indicated that the promoter enhancing disease progression based on data collected from of several gene transcriptions, chromatin remodeling, and brain cells, particularly astrocytes, in in vitro and in vivo histone modification is regulated by p300/CBP [175]. How- studies (Figure 1). Perhaps modifying the activity of glial ever, in astrocytes, the p300 is vital for the coactivation of cells to reduce their neurotoxic properties and enhance their several transcription factors such as AP-1 in the transcription neuroprotective effects may offer potential targets for thera- machinery, which has a significant role in the activation of peutic interventions in neurodegenerative diseases. Oxidative AP-1-mediated gene expression for proinflammatory medi- stress-induced signaling transduction pathways, including ators [173]. Previous results have indicated that p300 plays ROS, transactivation of EGFR or PDGFR, PI3K/Akt, MAPKs, an important role in BK-, IL-1𝛽-, and oxLDL-induced MMP- NF-𝜅B, and AP-1, that are associated with the CNS disorders 9 expression in astrocytes [21, 22, 96]. Recently, a study were discussed (Figure 4). Moreover, the review highlighted has shown that ROS-dependent p300 activation leads to current progress on the association of oxidative stress with the cPLA2 expression by cigarette smoke extract in human expression of various inflammatory genes, including MMP- tracheal smooth muscle cells [172]. Consistently, we have 9, cPLA2, COX-2, iNOS, and adhesion molecules and redox demonstrated that LTA induces p300/AP-1-dependent MMP- signal-sensitive transcription factors that may contribute to 9 expression via ROS-mediated pathway in astrocytes [27]. the development of the CNS inflammation and neurode- Moreover, oxidative stress activates NF-𝜅Bresultinginthe generative diseases (Figure 5). Possible therapeutic strategies expression of proinflammatory mediators through the acti- to target redox-sensitive signaling molecules, transcription vation of intrinsic HAT activity on coactivator molecules. factors, or cofactors are implicated based on the updated view Oxidative stress also inhibits HDAC activity and in doing of ROS-mediated regulation of inflammatory target genes in so enhances the expression of inflammatory genes which brain inflammation and neurodegenerative disorders. leads to a chronic inflammatory response. Oxidative stress can also increase complex formation between the coactivator Abbreviations p300 and the p65 subunit of NF-𝜅Bsuggestingafurtherrole of oxidative stress in chromatin remodeling [1]. Together, ROS: Reactive oxygen species these studies indicate that the oxidative stress-stimulated CNS: Central nervous system coactivator p300 may play a critical role in the expression of AD: Alzheimer’s disease inflammatory genes during brain inflammation and neurode- PD: Parkinson’s disease generative disorders. MMPs: Matrix metalloproteinases cPLA2: Cytosolic phospholipase A2 COX-2: Cyclooxygenase-2 7. Conclusions Nox2: NADPH oxidase 2 iNOS: Inducible nitric oxide synthase Glial cells maintain brain plasticity and protect the brain LPS: Lipopolysaccharide for functional recovery from injuries. Reactivation of glial IL-1𝛽: Interleukin-1 cells may promote neuroinflammation and neurodegenera- TNF-𝛼: Tumor necrosis factor-𝛼 tion (Figure 1) and, ultimately, the retraction of neuronal BBB: Blood-brain barrier synapses, which leads to cognitive deficits10 [ ]. Moreover, TLRs: Toll-like receptors redox signaling is a critical event in several inflammatory PGs: Prostaglandins diseases such as AD that precedes the formation of these NO: Nitric oxide disease pathologies. To date, although numerous effects A𝛽: 𝛽-Amyloid have been made to develop therapies based on antioxidants BK: Bradykinin in the past years, the actual benefits to the patients have ET-1: Endothelin-1 been very limited. It is likely due to lack of potency, late oxLDL: Oxidized low-density lipoprotein administration, and poor penetration into the brain cells [7, HO-1: Heme oxygenase-1 32]. Alternative strategies including searching for factors that CO: Carbon monoxide initiate endogenous antioxidants are necessary to improve RNS: Reactive nitrogen species the efficacy of treatment (Figure 2). Moreover, increased Xox: Xanthine oxidase oxidative stresses (ROS) by various proinflammatory factors, GPCR: G-Protein-coupled receptor such as cytokines, peptides, bacterial or viral infections, LTA: Lipoteichoic acid peroxidants, and other stress, serve as intracellular signals JEV: Japanese encephalitis virus in gene regulation and signaling transduction, in addition EV71: Enterovirus 71 to their deleterious effects on cellular components. Thus, AA: Arachidonic acid understanding how oxidative stress produces and modulates VCAM-1: Vascular cell adhesion molecule 1 expression of several genes that might help to develop effec- MAPKs: Mitogen-activated protein kinases tively therapeutic strategies for CNS diseases. First, the focus ERKs: Extracellular signal-regulated protein kinases BioMed Research International 13

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